Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development

• Published in: Developmental biology 2013-01, Vol.373 (2), p.373-382
• Main Authors: Mukhopadhyay, Anandaroop, Krishnaswami, Suguna Rani, Cowing-Zitron, Christopher, Hung, Nai-Jung, Reilly-Rhoten, Heather, Burns, Julianne, Yu, Benjamin D.
• Format: Article
• Language: English
• Subjects: alleles; Amplitude; Animals; Cell Differentiation; Cell Proliferation; Down-Regulation - genetics; explants; FGF; fibroblast growth factor receptor 2; Gene Expression Regulation, Developmental; Hair follicle; Hair Follicle - cytology; Hair Follicle - enzymology; Hair Follicle - growth & development; Hair Follicle - metabolism; hair follicles; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Mice; microarray technology; mitogen-activated protein kinase; Morphogen; morphogenesis; mutation; Oligonucleotide Array Sequence Analysis; oncogenes; Organ Size; phenotype; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - metabolism; RAS; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Shh; Signal strength; Signal Transduction - genetics; Skin - growth & development; Skin - metabolism; transcription (genetics); Transcription, Genetic
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2012.10.024

Activating mutations in the KRAS oncogene are associated with three related human syndromes, which vary in hair and skin phenotypes depending on the involved allele. How variations in RAS signals are interpreted during hair and skin development is unknown. In this study, we investigated the developmental and transcriptional response of skin and hair to changes in RAS activity, using mouse genetic models and microarray analysis. While activation of Kras (KrasG12D) in the skin had strong effects on hair growth and hair shape, steady state changes in downstream RAS/MAPK effectors were subtle and detected only by transcriptional responses. To model the transcriptional response of multiple developmental pathways to active RAS, the effects of growth factor stimulation were studied in skin explants. Here FGF acutely suppressed Shh transcription within 90min but had significantly less effect on Eda, WNT, Notch or BMP pathways. Furthermore, in vivo Fgfr2 loss-of-function in the ectoderm caused derepression of Shh, revealing a role for FGF in Shh regulation in the hair follicle. These studies define both dosage sensitive effects of RAS signaling on hair morphogenesis and reveal acute mechanisms for fine-tuning Shh levels in the hair follicle. ► Hair shaft defects result from ectodermal activation of Kras in mice. ► Shh is a RAS-responsive target gene. ► Shh levels acutely respond to FGF stimulation or MAPK/PI3K inhibition. ► Shh RNA has a short half-life and its levels are dependent on transcription. ► Ectodermal Fgfr2 regulates Shh levels in vivo.